Astragaloside Attenuates Atherosclerosis Coupled Inflammation Through miR-101/Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1)/p38 Signaling in Mice

2021 ◽  
Vol 13 (9) ◽  
pp. 1666-1673
Author(s):  
Zhidong Chen ◽  
Kankai Tang ◽  
Wei Xu ◽  
Fengqi Liu ◽  
Bingnan Zhu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
High Fat Diet ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Atherosclerotic Plaques ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Stable Plaque ◽  
Hepatocyte Steatosis

This study aimed at elucidating the effect of astragaloside on atherosclerosis coupled inflammation and potential mechanism in mice. C57BL/6J mice were maintained in high-fat diet (HFD) for 12 weeks to induce atherosclerosis, with or without treatment with astragaloside (50 mg/kg). In turn, serum biochemical parameters in mice were also evaluated. Multiple tissue stain assay, including HE, were employed to assess the pathological alterations in arteries, and blood inflammation mediators were examined using ELISA. Expressions of microRNA101 (miR-101), p-p38 and mitogen-activated protein kinase phosphatase-1 (MKP-1) in the arteries were evaluated by qPCR and Western blot. Finally, AML-193 cells were transfected by miR-101 mimics and inhibitors. Expression of miR-101, MKP-1 and downstream inflammation cytokines were then analyzed. High-fat diet (HFD) mice with astragaloside treatment exhibited reduced atherosclerotic plaques size evaluated by oil red o, improved hepatocyte steatosis, and increased collagen fibers in atherosclerotic plaques for more stable plaque. Further, astragaloside treatment suppressed miR-101 transcription and enhanced MKP-1 expression, thus restraining the secretion of inflammation factors in vitro. Moreover, the inhibited impact of astragaloside in inflammatory factors production was ineffective in the presence of miR-101 mimics in AML-193 cells stimulated by LPS. Astragaloside exerted an anti-inflammatory role through miR-101/MKP-1/p38 signaling, for reducing atherosclerotic plaques and alleviate inflammation damage in mice and AML-193 cell.

scholarly journals Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Deficiency Reduces Insulin Sensitivity in High-Fat Diet-Fed Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e106300 ◽  
Author(s):  
Jan Freark de Boer ◽  
Arne Dikkers ◽  
Angelika Jurdzinski ◽  
Johann von Felden ◽  
Matthias Gaestel ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Mitogen Activated Protein Kinase ◽  
High Fat ◽  
Mitogen Activated Protein

scholarly journals Cross-talk between IRAK-4 and the NADPH oxidase1

2007 ◽  
Vol 403 (3) ◽  
pp. 451-461 ◽  
Author(s):  
Sandrine Pacquelet ◽  
Jennifer L. Johnson ◽  
Beverly A. Ellis ◽  
Agnieszka A. Brzezinska ◽  
William S. Lane ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Free System ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Tlr4 Activation

Exposure of neutrophils to LPS (lipopolysaccharide) triggers their oxidative response. However, the relationship between the signalling downstream of TLR4 (Toll-like receptor 4) after LPS stimulation and the activation of the oxidase remains elusive. Phosphorylation of the cytosolic factor p47phox is essential for activation of the NADPH oxidase. In the present study, we examined the hypothesis that IRAK-4 (interleukin-1 receptor-associated kinase-4), the main regulatory kinase downstream of TLR4 activation, regulates the NADPH oxidase through phosphorylation of p47phox. We show that p47phox is a substrate for IRAK-4. Unlike PKC (protein kinase C), IRAK-4 phosphorylates p47phox not only at serine residues, but also at threonine residues. Target residues were identified by tandem MS, revealing a novel threonine-rich regulatory domain. We also show that p47phox is phosphorylated in granulocytes in response to LPS stimulation. LPS-dependent phosphorylation of p47phox was enhanced by the inhibition of p38 MAPK (mitogen-activated protein kinase), confirming that the kinase operates upstream of p38 MAPK. IRAK-4-phosphorylated p47phox activated the NADPH oxidase in a cell-free system, and IRAK-4 overexpression increased NADPH oxidase activity in response to LPS. We have shown that endogenous IRAK-4 interacts with p47phox and they co-localize at the plasma membrane after LPS stimulation, using immunoprecipitation assays and immunofluorescence microscopy respectively. IRAK-4 was activated in neutrophils in response to LPS stimulation. We found that Thr133, Ser288 and Thr356, targets for IRAK-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after LPS stimulation. We conclude that IRAK-4 phosphorylates p47phox and regulates NADPH oxidase activation after LPS stimulation.

Far1 and Fus3 link the mating pheromone signal transduction pathway to three G1-phase Cdc28 kinase complexes

1993 ◽  
Vol 13 (9) ◽  
pp. 5659-5669 ◽  
Author(s):  
M Tyers ◽  
B Futcher
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
G1 Phase ◽  
Transduction Pathway ◽  
Yeast Saccharomyces Cerevisiae ◽  
Alpha Factor ◽  
Mitogen Activated Protein

In the yeast Saccharomyces cerevisiae, the Cdc28 protein kinase controls commitment to cell division at Start, but no biologically relevant G1-phase substrates have been identified. We have studied the kinase complexes formed between Cdc28 and each of the G1 cyclins Cln1, Cln2, and Cln3. Each complex has a specific array of coprecipitated in vitro substrates. We identify one of these as Far1, a protein required for pheromone-induced arrest at Start. Treatment with alpha-factor induces a preferential association and/or phosphorylation of Far1 by the Cln1, Cln2, and Cln3 kinase complexes. This induced interaction depends upon the Fus3 protein kinase, a mitogen-activated protein kinase homolog that functions near the bottom of the alpha-factor signal transduction pathway. Thus, we trace a path through which a mitogen-activated protein kinase regulates a Cdc2 kinase.

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

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